| 1. |
- Kokkinou, Efthymia, et al.
(författare)
-
The single-cell transcriptional landscape of innate and adaptive lymphocytes in pediatric-onset colitis
- 2023
-
Ingår i: Cell reports medicine. - 2666-3791. ; 4:5
-
Tidskriftsartikel (refereegranskat)abstract
- Innate lymphoid cells (ILCs) are considered innate counterparts of adaptive T cells; however, their common and unique transcriptional signatures in pediatric inflammatory bowel disease (pIBD) are largely unknown. Here, we report a dysregulated colonic ILC composition in pIBD colitis that correlates with inflammatory ac-tivity, including accumulation of naive-like CD45RA+CD62L- ILCs. Weighted gene co-expression network analysis (WGCNA) reveals modules of genes that are shared or unique across innate and adaptive lympho-cytes. Shared modules include genes associated with activation/tissue residency, naivety/quiescence, and antigen presentation. Lastly, nearest-neighbor-based analysis facilitates the identification of most in-flamedand least inflamedlymphocytes in pIBD colon with unique transcriptional signatures. Our study reveals shared and unique transcriptional signatures of colonic ILCs and T cells in pIBD. We also provide insight into the transcriptional regulation of colonic inflammation, deepening our understanding of the poten-tial mechanisms involved in pIBD.
|
|
| 2. |
- Kvedaraite, Egle, et al.
(författare)
-
Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF
- 2024
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142−/low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142−/low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.
|
|
| 3. |
- Rolandsdotter, Helena, et al.
(författare)
-
Exclusive Enteral Nutrition : Clinical Effects and Changes in Mucosal Cytokine Profile in Pediatric New Inflammatory Bowel Disease
- 2019
-
Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 11:2
-
Tidskriftsartikel (refereegranskat)abstract
- Exclusive Enteral Nutrition (EEN) is the first-line treatment in children with Crohn's disease (CD) for induction of remission. However, the mode of action remains conjectural. The aim of this study was to investigate whether the effect of EEN is paralleled by changes in the mucosal cytokine profiles (MCP). Twelve children with new onset inflammatory bowel disease (IBD) received induction treatment with a polymeric EEN. We assessed clinical, endoscopic and histologic scoring before and after EEN. Twelve colonic cytokines were analyzed by Polymerase Chain Reaction (PCR) in six of the IBD patients at onset and after EEN as well as in six non-IBD control children at the diagnostic colonoscopy. Twelve children completed 6 weeks of EEN, except from one child who completed 4 weeks. At the control colonoscopy, 83% were in complete clinical remission. Changes were found in the MCPs of individual patients after EEN. In particular, children with IBD showed significantly higher values of Interleukin (IL)-12 (p = 0.008) and IL-23 (p = 0.02) compared to non-IBD controls at the diagnostic colonoscopy. Furthermore, an overall change in proinflammatory cytokines was noted in the IBD-group after treatment. Further studies are warranted to understand the role of EEN in MCP.
|
|
| 4. |
- Rolandsdotter, Helena, et al.
(författare)
-
Granulocyte and Monocyte Apheresis for Induction of Remission in Children With New-Onset Inflammatory Bowel Colitis
- 2018
-
Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - 0277-2116 .- 1536-4801. ; 66:1, s. 84-89
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of the study was to analyze the effect of granulocyte and monocyte apheresis (GMA) with mesalazine for induction of remission in pediatric patients with newly onset chronic inflammatory bowel disease (IBD) colitis.Methods: Thirteen pediatric patients with newly onset extensive IBD colitis were investigated per the ECCO/ESPGHAN IBD protocol. Of these 13, 12 received 10 treatments with Adacolumn (ADA) during a median of 6.25 weeks in combination with low-to-moderate doses of mesalazine, which was continued after apheresis. A control colonoscopy was performed 12 to 16 weeks after GMA treatment. Primary outcomes were mucosal healing (Mayo endoscopic score) and histopathologic grading of biopsies. A secondary outcome was disease activity as measured by the Pediatric Ulcerative Colitis Activity Index.Results: Twelve children (6 girls) with a median age of 14.6 years and a median duration of symptoms at diagnosis of 3.2 months received all planned 10 treatment sessions with ADA. Ten of 12 patients had pancolitis and 2 of 12 extensive colitis. A final diagnosis, however, indicated ulcerative colitis in 10 children and Crohn disease in 2 children. At control colonoscopy, 8 of 12 children were in clinical remission and the Mayo endoscopic score showed significant improvement in 9 of 12 patients (P = 0.006). Complete microscopic remission, according to the Geboes score, was observed in 2 patients.Conclusions: In this small study GMA for induction of remission of newly onset pediatric IBD colitis was effective in 8 of 12 patients. Further controlled studies are warranted to confirm the efficacy of this treatment model.
|
|
| 5. |
- Rolandsdotter, Helena J
(författare)
-
Pediatric inflammatory bowel disease : clinical and immunological aspects on remission treatment
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background - Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are lifelong conditions characterized by abdominal pain, bloody diarrhea and fatigue. The incidence and prevalence are increasing worldwide, with approximately 10-20% of all IBD cases diagnosed during childhood. The etiology is considered multifactorial but is not completely understood. However, genetic susceptibility, environmental factors and disturbed immunological function appear to contribute to the development of IBD. The treatments of pediatric CD and UC are only in part the same. Unfortunately, we still frequently use high dosage of corticosteroids, and we do not practice personalized medicine because of a lack of knowledge about which treatment best suits the individual patient. In our ambition to better understand the pathophysiology of IBD and the mode of action of established therapies, as well as to determine new therapy strategies, we studied the clinical effect of Infliximab (IFX) in children on maintenance treatment and the therapeutic effect of granulocyte and monocyte apheresis (GMA) in children with newly onset IBD. In addition, children with CD were treated with exclusive enteral nutrition (EEN) as induction of remission therapy. Finally, we studied the immunological profile in blood at onset and in intestinal mucosa at onset and after GMA and EEN treatment. Methods and results - We investigated the association between s-IFX trough levels and antibodies to IFX (measured with ELISA, enzyme-linked immunosorbent assay) to clinical indices and CRP, ESR, albumin and F-calprotectin in 45 children om maintenance IFX treatment. The mean s-IFX trough levels were significantly higher during remission than in active disease, correlating to the clinical indices, ESR, CRP and albumin. The development of antibodies to IFX strongly correlated to undetectable s-IFX and active disease (Paper 1). In paper II (pilot study), 12 children with newly IBD colitis received 10 sessions with GMA together with a low to moderate dose of mesalazine as induction of remission. A control colonoscopy (CC) was performed 12 to 16 weeks post-treatment, in which the endoscopic Mayo score showed significant improvement in 9/12 children (8/12 were in clinical remission). In seven of these children (paper V), the expressions of 14 cytokines were investigated (by real time polymerase chain reaction, PCR) in the intestinal mucosa at onset and after the combination therapy of GMA and mesalazine. Significant decreases were seen in CSF-2, TNF-α, IL-23α, IL-1β, IL-36γ, IL-10 and TGFβ1 after treatment while significant decreases were observed in the clinical index and Mayo endoscopic score. Compared with the IBD patients, significantly lower levels of IL-12β and IL- 23α were found in the six non-IBD controls at onset. In paper III, we characterized the chemokine receptor landscape in 45 children (UC: n=16, CD: n=12 and healthy controls: n=17) using flow cytometry. By defining a diagnostic algorithm based on these markers, we could distinguish UC from CD in >92% of the studied children with newly onset IBD. In paper IV, 12 children with newly onset IBD were treated with six weeks of EEN as induction of remission therapy. Eleven of the 12 patients successfully completed the treatment. A CC after completion of EEN showed significant decreases in endoscopic scoring (SES-CD) and 83% of the patients were in clinical remission. Additionally, in six of the children mucosal cytokines were measured by real time PCR at diagnosis and at CC. An overall decrease (though not statistically significant) in pro-inflammatory cytokines, as well as both decreases and increases in the regulatory cytokines, were seen after EEN therapy. Conclusions - We conclude that an active approach is needed in the care of children with IBD to achieve and maintain remission. Our findings reveal that the children on IFX maintenance treatment were only in remission in 28% of the visits. The combination of GMA and mesalazine was found to be a safe and effective treatment in children with newly onset IBD. It seems plausible to speculate that the decreases in mucosal cytokines after the induction of remission may explain the good clinical result. Moreover, a change in the mucosal cytokine profile after induction of remission with EEN was observed. By investigating the chemokine receptors, we found a possible prognostic IBD marker, and by analyzing the cytokine profiles in mucosal biopsies, we have extended the knowledge of immunological phenotypes in children with IBD. Suggestions for the future - Corticosteroid-free treatment alternatives must be explored and those currently in use must be optimized. To conclude, more and bigger studies are needed to explore the pathogenesis of IBD to determine new treatment alternatives.
|
|
| 6. |
- Rolandsdotter, Helena, et al.
(författare)
-
Mucosal Cytokine Profiles After Induction Therapy With Granulocyte/Monocyte Apheresis in New-onset Inflammatory Colitis
- 2018
-
Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - 0277-2116 .- 1536-4801. ; 66:4, s. E103-E107
-
Tidskriftsartikel (refereegranskat)abstract
- Granulocyte/monocyte apheresis (GMA) selectively removes circulating granulocytes and monocytes; important producers of proinflammatory cytokines. Seven children with new-onset inflammatory bowel disease (IBD) colitis were treated with GMA together with mesalazine, and had significant decreases in Pediatric UC Activity Index (P=0.018) and Mayo endoscopic score (P=0.013). We investigated the colonic mucosal cytokine profiles (analyzed with real-time polymerase chain reaction), before and after induction treatment, and in 6 non-IBD controls. Significant decreases were seen in Colony Stimulating Factor 2 (P=0.018), tumor necrosis factor- (P=0.028), interleukin (IL)-23 (P=0.043), IL-1 (P=0.028), IL-36 (P=0.018), IL-10 (P=0.028), and transforming growth factor beta 1 (P=0.043) after treatment. In 6 non-IBD controls there were significantly lower levels of IL-12 (P=0.023) and IL-23 (P=0.046) compared to the patients with IBD at onset, and IL-22 (P=0.088) and IL-36 (P=0.062) showed lower values without reaching significant differences. We speculate that the decreases in colonic mucosal cytokine profiles after treatment may explain the observed clinical efficacy in the GMA-treated children with IBD.
|
|
